Attempts at dual blocking of biochemical events in cancer chemotherapy.

Abstract

A series of chemical events in which citrovorum factor may act as a coenzyme were examined to determine if multiple blocks in this area might provide for potentiated antileukemic activity in the mouse. The theoretical basis for this effort hinged upon use of combinations of agents which might be expected to provide for sequential or concurrent blocks in biochemical reactions leading to a single end product. It was observed that ethionine, which is without antileukemic activity alone, significantly potentiates the antileukemic activity of A-methopterin. The activity of A-methopterin plus 8-azaguanine was greater than that of A-methopterin alone, and a combination of A-methopterin plus ethionine plus 8-azaguanine was more effective than any dual combination of these agents against L1210 leukemia. Methionine was effective in preventing the potentiation of A-methopterin by ethionine. Possible mechanisms involved in use of combinations of a folic acid, a methionine antagonist, and a purine antagonist, i.e., sequential or concurrent blocking, are discussed. Ethionine was shown to be a good inhibitor of Adenocarcinoma 755, but to be ineffective against Sarcoma 180 in mice.